D1-Receptor-related priming is attenuated by antisense-meditated 'knockdown' of fosB expression.
Administration of dopamine receptor agonists to rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway produce changes in the denervated striatum that enable a subsequent injection to elicit more vigorous circling. The molecular basis for this behavioural phenomenon, termed priming, is unknown. D1-receptor-related priming has been associated with a profound elevation of immediate-early gene (IEG) expression in the denervated striatum. Since immediate-early genes encode known transcriptional regulating factors, this observation has led to the suggestion that IEG induction may play a role in the gene signaling pathways which mediate priming. In the present study, we addressed the role of induction of the IEG fosB in dopamine agonist-induced priming by examining whether inhibition of the synthesis of FosB proteins (FosB and DeltaFosB) by intrastriatal delivery of an antisense oligonucleotide to fosB reduced apomorphine-induced priming. Intrastriatal delivery of an antisense, but not a random, oligonucleotide to fosB 18 and 6 h before apomorphine reduced the ability of this mixed D1¿D2-like receptor agonist to prime circling induced by the specific D1-like receptor agonist SKF 38393. Immunohistochemical analysis revealed that only the antisense oligonucleotide blocked apomorphine-induced increases in FosB-like immunoreactivity in the denervated striatum. In contrast, apomorphine-induced increases in JunB-, NGFI-A- and Fos2-16-like immunoreactivities were unaffected by either the antisense or random oligonucleotides, indicating that the antisense oligonucleotide attenuated apomorphine-induced priming by selectively blocking the synthesis of FosB proteins. Taken together, these findings suggest that fosB induction in the denervated striatum plays a role in mediating D1-receptor-related priming. Dopamine replacement therapy for Parkinson's disease is often complicated by the development of dyskinetic side effects. Results from the present study suggest that D1-receptor-mediated increases in fosB expression may be involved in those intracellular events responsible for the generation of these debilitating side effects.
Crocker
S J
SJ
Department of Pharmacology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Morelli
M
M
Wigle
N
N
Nakabeppu
Y
Y
Robertson
G S
GS
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology*; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D051766:Early Growth Response Protein 1; D005786:Gene Expression Regulation / Q000187:drug effects; D017781:Genes, Immediate-Early / Q000187:drug effects; D017874:Immediate-Early Proteins; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D016627:Oxidopamine; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000502:physiology*; D013239:Stereotyped Behavior / Q000187:drug effects; D014157:Transcription Factors / Q000096:biosynthesis; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D016376:Oligonucleotides, Antisense; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D017447:Receptors, Dopamine D1; D014157:Transcription Factors; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D016627:Oxidopamine; D001058:Apomorphine